3-Hydroxy-3-(3,4-methylenedioxyphenylalkyl-3,4-dihydro-2H-1,5-benzodioxepin products

ABSTRACT

3-Hydroxy-3-(substituted-aminoalkyl)-3,4-dihydro-2H-1,5benzodioxepin products are described that exhibit Beta adrenergic stimulating properties and are therefore suitable for use as bronchodilating agents. The products are prepared essentially by three principal routes from 3-oxo-3,4-dihydro-2H1,5-benzodioxepins. By one route the 3-oxobenzodioxepin is treated with a nitroalkane to give a 3-hydroxy-3nitroalkylbenzodioxepin the nitro group of which is reduced to an amino and the resulting compound reacted with an aldehyde or ketone to introduce the desired substituent into the amino function. By a second route the 3-oxobenzodioxepin is reacted with an alkali metal nitrile to form the cyanhydrin which upon reduction forms the 3-hydroxy-3-aminoalkyl-benzodioxepin that can be treated with a ketone or aldehyde to give the desired products or can be reacted with sodium nitrite or other agent to form a 3spiro-benzodioxepin-2&#39;&#39;-oxirane which upon reaction with an amine provides the desired product. The Beta -spiro-benzodioxepin-2&#39;&#39;-oxirane also can be obtained by treatment of the 3-oxo-benzodioxepin with a sulfurylide. A fourth method involves forming a benzodioxepin-3-spiro-3&#39;&#39;oxazolidin-4-one which upon treatment with dilute alkali gives the desired 3-hydroxy-3-(substituted aminoalkyl)-3,4-dihydro-4H1,5-benzodioxepin. The intermediate oxazolidinone compounds can be treated if desired with various agents to attach substituents on the benzenoid moiety of the starting substance. These oxazolidinones exhibit Beta -stimulating and skeletal muscle relaxant properties.

United States Patent [191 Wasson et a1.

[451 May6, 1975 1 3-HYDROXY-3-(3,4-

METHYLENED1OXYPHENYLALKYL-3,4- DlHYDRO-2H-l,S-BENZODIOXEPIN PRODUCTS [75] Inventors: Burton K. Wasson, Valois; Haydn W. R. Williams, Dollard Des Ormeaux, Quebec, both of Canada [73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Nov. 21, 1973 21 Appl. No.: 417,870

Related U.S. Application Data [60] Division of Ser. No. 249,422, May 1, 1972, Pat. No. 3,812,150, which is a division of Ser. No. 832,879, June 9, 1969, Pat. No. 3,700,691, which is a continuation-in-part of Ser. No. 755,442, Aug. 26, 1968, abandoned.

Primary Examiner-John D. Randolph Attorney, Agent, or FirmDavid L. Rose; J. Jerome Behan; Erma R. Coutts [57] ABSTRACT 3-Hydroxy-3-(substituted-aminoalkyl )-3,4-dihydro- 2H-l,5-benzodioxepin products are described that exhibit fi-adrenergic stimulating properties and are therefore suitable for use as bronchodilating agents. The products are prepared essentially by three principal routes from 3-oxo-3,4-dihydro-2H-l ,5- benzodioxepins. By one route the 3-0x0benzodioxepin is treated with a nitroalkane to give a 3-hydr0xy-3- nitroalkylbenzodioxepin the nitro group of which is reduced to an amino and the resulting compound reacted with an aldehyde or ketone to introduce the desired substituent into the amino function. By a second route the 3-oxobenzodioxepin is reacted with an alkali metal nitrile to form the cyanhydrin which upon reduction forms the 3-hydroxy-3-aminoalkylbenzodioxepin that can be treated with a ketone or aldehyde to give the desired .products or can be reacted with sodium nitrite or other agent to form a 3-spirobenzodioxepin-2'-oxirane which upon reaction with an amine provides the desired product.

The B-spiro-benzodioxepini-oxirane also can be obtained by treatment of the 3-0xo-benzodioxepin with a sulfurylide. A fourth method involves forming a benzodioxepin-3-spiro-3 -oxazolidin-4-one which upon treatment with dilute alkali gives the desired 3-hydroxy-3-(substituted aminoalkyl)-3,4-dihydro-4H-1,S-benzodioxepin. The intermediate oxazolidinone compounds can be treated if desired with various agents to attach substituents on the benzenoid moiety of the starting substance. These oxazolidinones exhibit B-stimulating and skeletal muscle relaxant properties.

7 Claims, No Drawings 1 3-HYDROXY-3-(3A- METHYLENEDIOXYPHENYLALKYL-3.4- DIHYDRO-ZH- l .S-BENZODIOXEPIN PRODUCTS This is a division of application Ser. No. 249.421. filed May I. 1972. now US. Pat. No. 3.8l2.l5(). granted May 21. I974. which in turn was a division of the then copending application. Scr. No. 832,879. filed June 9. I969. now U.S. Pat. No. 3.700.691. granted Oct. 24, 1972. which in turn was a continuation-in part of the then copending application. Ser. No. 755,442. filed Aug. 26. I968. now abandoned.

This invention is concerned with 3.3-disubstituted benzodioxepins which exhibit B-adrcnergic stimulating properties which make them uniquely suitable for use as broncho-dilating agents.

The novel 3.3-disuhstituted benzodioxepins of this invention can be illustrated by the structural formula it ie it l ca-ukpfi R o I and pharmacologically acceptable salts thereof wherein R is selected from hydrogen, hydroxy, lower alkyl (C and lower alkoxy (C R is selected from hydrogen, halogen particularly chloro and bromo. lower alkyl (C nitro. amino. monoor di-lower alkylamino. acrylamino wherein the acyl radical is the residue of an alkyl (C sulfonic acid or an alkyl (C, carboxylic acid, lower carboalkoxyamino. hydroxy or lower alkoxy (C,. =,l; X and X are selected from hydro gen, lower alkyl (C and halogen; R and R can be the same or dissimilar and are each separately selected from hydrogen. lower alkyl [C phenyl or phenyllower alkyl (C lower cycloalkyl, pyridyl and pyridyl-lower alkyl (C R is selected from hydrogen and lower alkyl (C,.;,); and the grouping -NR"R represents the amino group or a monoor di-substituted amino group or a nitrogen containing heterocyclic group and in particular an NR 'R"' group where R represents hydrogen. lower alkyl (C and substituted lower alkyl such as 2-phcnyl-Z-hydroxycthyl. and R" represents 1 lower alkyl having advantageously from 1 to carbon atoms and being either straight or branched chain. and being either unsubstituted or substituted with one or more groups selected from (at) amino or monoor diJower-alkyl (C amino. or the amino substituent can be no ant-crux: 5

wherein R. R and X ha\c the above assigned meanings. (b) cycloalkyl having from 3 to (1 carbon atoms. (c) lower alkoxy having from 1 to 3 atoms. (d) hydroxy substituted lower alkoxy having from 1 to 3 carbon atoms. (e) hydroxy. (f) phenyl or monoor poly substituted phenyl wherein the substituents are selected from halo especially chloro or bromo. hydroxy and lower alkoxy (C or wherein the substituted phenyl is the 3,4mcthylenedioxyphenyl. (g) a heterocyclic substituent such as an indolyl. morpholino or 1.2.5- thiadiazolyloxy. (2) a cycloaliphatic such as a cycloalkyl having from 3 to 10 carbon atoms such as cyclopropyl. cyclohutyl. cyclopentyl. cyclohexyl. tricyclodecane such as adamantyl and the like. or a phenyllowercycloalkyl as phenyl-cyclohexyl. (3) lower alkc nyl having from 3 to 5 carbon atoms. (-1) lower alkynyl having from 3 to 5 carbon atoms. (5) phenyl or substituted pheny] wherein the monoor polysubstituents are selected from a halogen such as chloro and hromo. lower alkyl (C and lower alkoxy ((1 (h) a heter ocyelic substituent such as Z-pyridyl. 17) the residue of a guanidine moiety of the structure -c-mm wherein R is hydrogen. lower alkyl. ben7yl or phenyl or substituted phenyl wherein the substituent is one or more groups selected from halo. especially chloro or bromo. lower alkyl (C or lower alkoxy (C (8) the benzodioxepin radical WW. 1 W22 .2

Reduction Reduecioa According to the above reaction scheme it is seen that the desired 3.4dihydro-2H-l.5-benzodioxepin. product it is obtained from the 3-keto compound A by one of two methods depending upon whether R is hydrogen or whether it represents a lower alkyl group of from 1 to 4 carbons. Additionally the 3-keto compound A can be directly converted to the 3-spiro-2'- oxirane E by use of a sulfur ylide.

When R" is hydrogen, the 3-keto intermediate A in an acidic solvent is caused to react with aqueous hydro gen cyanide conveniently generated in situ from sodium or potassium cyanide to provide the 3hydroxy-3- cyano intermediate C which is separated and reduced to provide the 3-hydroxy-3-aminoallcyl intermediate D. Treatment of intermediate D with acetone or other ketone or aldehyde that will yield the group R upon reduction provides the desired provide l. Intermediate D" also can be treated with an alkali nitrite to form the 3spiro-2-oxirane E which when reacted with the desired amine forms product I.

The first step of the above procedure that is treatmerit ofthe 3-keto compound A with aqueous alkali cyanide. advantageously is carried out in the presence of acetic anhydride or other acidic solvent. erg. acetic acid or alternatively with anhydrous hydrogen cyanide. The reduction of intermediate C can be either a catalytic or chemical reduction; catalytic reduction preferably being carried out with a transition metal catalyst such as platinum, palladium, nickel ruthenium. rhodium and the like in a mixture of a lower alkanol (C and acetic acid supplemented if necessary with a trace of mineral acid, i.e. hydrochloric acid, or if desired chemical reduction can be effected with a metal hydridc advantageously lithium aluminum hydride or other metal hydrides. preferably in diethyl ether or tetrahydrofuran. Each method affords good yields of product D.

Intermediate D then can be converted to the desired 3,3-disubstituted benzodioxepin l of this invention by either of two routes. One of the routes employed for preparing product I wherein R is hydrogen. involves the reaction of intermediate D with a ketone or aldehyde that will yield the group R and subsequent reduction advantageously carried out by hydrogenation in the presence of a transition metal catalyst in an organic -3-hydroxy-3-hydroxymethyl solvent such as a lower alkanol as ethanol propanol, butanol or isomers thereof and the like, employing acidic conditions when required or chemical reduction with sodium borohydride can be employed.

The second more general method for preparing product l where R and R have the meaning given above involves the reaction of intermediate D with an alkyl ni trite or with nitrous acid generated in situ from an alkali metal nitrite (sodium or potassium nitrite being quite suitable) advantageously carried out in an aqueous medium in the presence of an organic acid, acetic acid being preferred. and advantageously with cooling to provide a 3-spiro-2'-oxirane E as well as the analog. The novel 3hydroxy-3-hydroxymethyl products also exhibit B-adrenergic stimulating properties, and constitute another feature of this invention. The 3-spiro-2-oxirane E obtained then is reacted with the amine, HNR R". advantageously in the presence of an organic solvent such as a lower alkanol at ambient temperature to give the benzodioxepin I. When R represents the amidine group.

these products also can be prepared by reaction of product I wherein R and R represent hydrogen with an S-loweralkylisothiuronium salt of the structure S- allay/l v mac-MR advantageously with heating up to about the reflux temperature of the reaction mixture. When NR R"' in product I is the l-aziridinyl group treatment of said compound with sodium thiocyanate under acid conditions (pH no greater than 4) provides product 1 5 wherein -NR R is the 3[ liminothiazolidinyl) group.

Product I wherein R. R. X and R represent hydrogen can be employed as starting materials to prepare end products wherein R. R' and X are other than hydrogen and particularly where R is nitro, amino, lower acrylamino and hydroxy. These latter compounds can be prepared by the methods described above or by initially treating a 3hydrox v-3-( RN H-CH benzodioxepin with phosgene in the presence of a base. Phosgene advantageously in admixture with chloroform is added dropwise with stirring to a cooled solution of the benzodioxepin in the same solvent. The 3-spiro-5'-oxazolidin-2'-one obtained is admixed with acetic acid, cooled to the freezing point and treated dropwise with a mixture of nitric acid and sulfuric acid to provide the corresponding 7-nitro-3-spiro-5'- oxazolidin-2-one compound which in the presence of dilute alkali. as aqueous sodium or potassium hydroxide. gives the desired 7 nitro-3-hydroxy-3-(R- NHCH )benzodioxepin, l-a.

Catalytic reduction of La or its intermediate 7-nitro- 3-spiro-5'-oxazolidin-2'-one, advantageously with palladium or Raney Nickel provides the corresponding 7-amino derivative. The 7-amino-3-spiro-5'-oxazolidin- 2'-one when treated with aqueous alkali gives the 7- amino-3hydroxy 3-(RNHCH )benzodioxepin. l-b.

Product l-a also can be converted in the 7-amino analog, l-b. or to the 7-lower acylamino by first reacting l-a with an aldehyde YCHO, wherein Y can be lower alkyl, phenyl or the residue of any commercially available aliphatic or aromatic aldehyde. to form the 7 nitro2'-Y- 3-spiro 5-oxazolidine which. upon reduction as described above. gives the corresponding 7-amino compound which can either be treated with aqueous alkali to provide product l-b or treated with a lower alkyl sulfonyl halide or a lower alkanoyl halide to give the corresponding 7-acylamino-2'-Y-3-spiro-5'-oxazolidine which when treated with acid. especially with a mineral acid or strong organic acid, gives the 7-acylamino3- hydroxy-3-(R NHCH )benzodioxepin, l-c.

Diazotization of the 7-amino-3-spiro-5'-oxazolidin- 2'-one, prepared as described above. gives the corresponding 7-hydroxy compound which, in the presence 6 of base, such as barium hydroxide gives 3.7-dihydroxy- 3-(R NHCHflbenzodioxepin. l d.

The 6- and/or 7-hydroxy-benzodioxepins. I. also can be prepared from the corresponding 6- and/or 7-alkoxybenzodioxepins by treatment with strong mineral acid.

The 3-spiro-2'-oxirane E can also be prepared by treatment of the 3-Keto compound A with either dimethylenesulfonium methylide or dimcthylsulfonium methylide either with cooling or at a temperature up to ambient temperature. ln practice. the dimethyloxosulfonium methylide is prepared under nitrogen from sodium hydride, trimethyloxosulfonium iodide and di methyl sulfoxide. The ketone. A. is added slowly to the mixture at ambient temperature and the mixture stirred for about 24 hours. The dimethylsulfonium methylide advantageously is prepared from butyl lithium and trimethylsulfonium iodide in tetrahydrofuran. The ketone A then is added and the reaction mixture held at 0 C. for 1 hour and then for a short period at ambient temperature Isolation in each instance provides the desired 3-spiro-2-oxirane. E.

To prepare the products wherein R is a lower alkyl group, the ketone A initially is reacted with a nitroalkane to give intermediate B which upon reduction provides intermediate D. The reaction of the ketone A with the nitro-alkane advantageously is carried out in ethanol or other lower alkanol or ether in the presence of sodium ethoxide or other alkali metal alkoxide to give a salt of B from which the compound is liberated by treatment with a weak acid such as acetic acid. The reduction of intermediate 8 to form D is effected advantageously in ethanol (or other lower alkanol l acetic acid with hydrogen and Raney Nickel or palladium.

While the unsubstituted 3-keto compound A is known. it was obtained in low yields as a by-product in the preparation of l .4-benzodioxane-3-carboxylic acid. All attempts by these investigators to prepare the 3- ketobenzodioxepin either failed or provided very small yields of the desired product. A process thus had to be devised for the preparation of this ketone which has been found to give very high yields of compound A. This novel synthetic route for the preparation of the 3- keto compound A can be illustrated as shown in Flow Diagram ll.

FLOW DIAGRAM II hydrolysi s and decarboxylatlon X 2 R3 x 0 R H H Azacycle 2 3 (when/R land R X, X

t R o,

R H H According to the reaction scheme illustrated in Flow Diagram ll the catechol starting material E is con verted to the B-keto product A by initial reaction with a haloalkanonitrile or a haloalkanoic acid ester.

Treatment of the catechol E with a halo-aectonitrile of the structure XCR-RCN. to afford the l 2 bis-(eyanoalkoxy )-benzene F is carried out in one step when R and R" each represent hydrogen however. when it is desired to form product F wherein R and R are other than hydrogenthen the catechol (R=R=H) initially is treated with one equivalent of haloacetonitrile. the ortho cyanomethoxyphenol isolated and then reacted with the haloalkanonitrile to give F wherein R and/or R are other than hydrogen.

When R or R is other than hydrogen then it is preferred to use the appropriately substituted salicylaldehyde which is treated with the appropriate haloalk anonitrile. and the resulting compound oxidized by peracetic acid followed by mild hydrolysis to give the orthocyanoalkoxyphenol which then is treated with haloacetonitrile to provide Fr Product F then is cyclized by treatment with a mixture of sodamide and a solvent selected preferably from dimethyl sultoxide (DMSOL dimethylformamide (DMF).stilfolai1c. bene 2ene toluene or xylene or by treatment with an alkali metal tertrbutoxide or other alkali metal. ti-all-tanolate in DMSO. DMF. benrene. toluene. xylene, sulfolane or a twalkanol corresponding to the alkanolate employed or by treatment with sodium or potassium lower alkanolate. sodium hydride. potassiunrsodium amalgam oil hydrolysis and deca rboxylation Alkylati on and hydrolysis (l:l) lithio or sodio-N-methylaniline. to form the 3-amino-4-cyano-2H-l 5 benzodioxepin, Gr Best results are obtained when this step is carried out in an inert atmosphere such as under nitrogen or other inert gas such as argon or other usual inert gas. intermediate 0 is hydrolyzed and decarboxylated to the ketone A either by first refluxing in aqueous acetic acid followed bu refluxing with phosphoric acid, or by acid alcoholysis followed by heating in aqueous alkanol to effect hydrolysis and decarboxylation. While intermediate G is illustrated as having the structure 3-amino-4-cyano, its tautomcr. 3-imino-4-cyano-3,4-dihydro-2H-l 5- benzodioxepin may also be present. It is understood that when X XK R and/or R is/are other than hydrogen. additional isomers are possible However, upon hydrolysis with concomitant decarboxylation by either of the above procedures all tautomers or isomers are converted to the 3-keto compound A.

When X,X'. and all Rs in compound A are hydrogen, this product, ifdesired can be reacted with an azacycle such as morpholine. piperidine, pyrrolidine. and the like to give the 3a2acyclic substituted compound H which when treated with an alkylating agent as a lower alkyl iodide or bromide dialkylsulfate 0r trialkyloxoniumtetrafluoroborate provides the desired 2-mono-substitutcd-3-kcto compound A.

The second of the principal methods for making compound A from the catechol E involves initial reaction of E with a halo-alkanoic acid ester, haIo-CR R C(Lalkyl. to give the ltZ-bis-alkoxycarbonylalkoxyben- Yene. F When R and R" in compound F are each hydrogen. compound F is produced in one step. When R" and/or R are other than hydrogen. then the cateehol (X=X =R R'=H) initially is treated with haloacetic acid ester, the ortho-alkoxycarbonylmethoxyphenol isolated and then reacted with a haloalkanoic acid ester to give F wherein R and/or R are other than hydrogen. When X.X, R and/or R is/are other than hydro gen. preferably the appropriate salicylaldehyde is reacted with Y-CR 'R' CO alkyl wherein R and/or R is other than hydrogen and the resulting compound oxidized by peracetic acid followed by mild hydrolysis to give the orthoalkoxycarbonylalkoxyphenol or the corresponding acid which can be rcesterified. The ester then is treated with an alkyl haloacetate to provide intermediate F Cyclization of compound F to form G is effected by substantially the same method described above for the cyclization of F to provide G. Hydrolysis and decarboxylation of G by acid hydrolysis in a lower alkanol advantageously by employing aqueous hydrochloric acid in methanol or ethanol followed by heating gives the desired 3-keto compound A.

The pharmacologieally acceptable salts of the benzodioxepins of this invention are prepared by the reac tion of product I with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, formic, acetic, succinic, lactic, malic, tartaric, citric, maleic, phenylacetic. benzoic, salicyelic, or p-toluenesulfonic acid or similar acids that are known to provide pharmacologically acceptable salts.

The benzodioxepins however can be employed in pharmaceutical formulations either in the form of free bases or in the form of their acid addition salts in conjunction or admixture with organic or inorganic solid or liquid pharmaceutical exipients. These pharmaceutical formulations can be in the form of tablets, solutions. suspensions. emulsions, or aerosols suitable for oral or topical administration.

Unlike hitherto known bronchodilators which gener ally are short acting. the benzodioxepin products of this invention exhibit a long duration of activity. The compounds were found when tested according to accepted and standard laboratory procedures in guinea pigs to be orally effective within a dosage range of from about 1 mg. to about mg/kg. and when administered intravenously the effective dosage range was between lt) microg/kg to 2mg./kg. At these dosages the products were acceptably tolerated by the animals.

The 3'-R-6-R-7-R -3.4-dihydro-2Hl ,5- benzodioxepin-3-spiro-5'-oxazolidin-2'-one compounds prepared in the synthesis of the principal products of this invention. are also novel and form another feature ofthis invention. ln addition to exhibiting bronchodilating properties. these compounds also exhibit muscle relaxing properties and are therefore useful in the relief of spastic states.

The following examples will illustrate the preparation of representative products of this invention prepared by the above-described procedures. It will be understood that while all of the compounds can be prepared by the procedure described in the following examples, modifications of the procedural steps which would be obvious to the skilled chemist can be employed. The following examples therefore are not to be considered as limiting the preparation of any particular compound to the precise procedural steps described in the examples wh ch are provided solely to illustrate the best mode currently known to applicant.

Where the term bcnzodioxepin is employed in the disclosure and claims it is to be understood to mean 3,- 4-dihydro-ZH- l ,5benzodioxepin.

The following examples describe the preparation of the novel products of this invention by the route A C D l illustrated in Flow Diagram EXAMPLE l 3-Hydroxy-3-isopropylaminomethyl-3.4-dihydro2H 1.5 benzodioxepin Hydrochloride Step A: Preparation of l.2-di-(cyanomethoxy)benzene A mixture of 99 g. (0.9 moles) of catechol, 90.6 g. (1.2 moles) of chloroacetonitrile. lhX g. (1.22 moles) of finely powdered potassium carbonate. and 600 ml. of acetone is refluxed with stirring for 1 hours. The mixture then is treated with 45.3 g. (0.6 mole) of chloroacetonitrile and 84 g. (0.608 mole) of potassium carbonate, and refluxed for a further 3.5 hours. The mixture is filtered. the solids washed with ISO ml. of acetone and the combined filtrate evaporated in vacuo to give an oil. The oil which crystallizes is recrystallized from ethanol-water (8:1 to give 138 g. (8L5 percent) of l,2-di-(cyanomcthoxy )henzene. mp. 85.(l-Rh.5 C. Further recrystallization from the same solvent system affords the product melting at 850 85.51.

Found. ti-l l7. H, 4.48. N. I434 Step B: Preparation of 3-amino 4-cyano2H-l,5- benzodioxepin Sodamide (49.2 g., 1.26 mole) is added with stirring under nitrogen to 370 ml. of dry diniethyl sulfoxidc. After the initial vigorous e\olution of ammonia has subsided the solution is heated one-half hour at (10 C. A solution of 115.8 g. (dole mole) of l,Z-dbtcyanomethoxy)ben7ene in 246 ml. of dimethyl sulfoxide is added with stirring and cooling (water bath at ambient temperature) during l hour and the reac tion mixture stirred for a further 2 hours at ambient temperature. A mixture of 81.5 ml. of acetic acid and 246 ml. of water is added slowly accompanied by stirring and cooling. The mixture is poured into 1.2 liters of water and the tan-colored solids collected. The solids are recrystallized from chloroform to give 75.5 g. percent) of B-amino-J-cyano-ZH- l .5- benzodioxepin. mp. l67l69 C. Further recrystallization from chloroform affords the product melting at l68-l69 C.

Found: C. (0.80; H, 4.15, N. I4 70.

Alternatively the above 3-amino-4-eyano-ZHl.5- benzodioxepin can be prepared as follows.

A solution of 9.4 g. (50 millimoles) of l,Z-di-(cyanomethoxy)benzenc in 20 ml. of dimethyl sulfoxide is added under nitrogen to a stirred mixture of I23 g. (llll millimoles) of potassium tert-butoxidc in 30 ml. of dimethyl sulfoxide cooled in a water bath at ambient temperature. The mildly exothermic reac tion raises the internal temperature of the mixture to 42 C. The mixture is stirred a further 2 hours and a solution of 6.6 ml. of acetic acid in 20 ml. of water added slowly with cooling. (Alternatively, the reaction mixture can be poured into the aqueous acetic acid solution] The product is precipitated by pouring the mixture into IOU ml. of water. The beige-colored solid is collected. washed with water. and air dried to give 9.5 g. ofcrude product. m.p. 148-154 C. The crude product is recrystallized from ZUU m1. of chloroform to afford 5.8 g. (62.7 percent) of 3-amino4-eyano-2H-1.5 benzodioxepin. A mixed melting point with the product obtained above gave no depression. Step C: Preparation of 3-oxo3.4-dihydro-2H- l .5 bcnyodioxepin A mixture of 16.(l g. (85.1 millimoles) of 3-amino-4 cyanoQH-l.S-benzodioxcpin. 18 m]. of water. and 300 ml. of acetic acid is refluxed one-half hour. The mix ture is treated dropwise with 120 ml. 85 percent phosphoric acid and then refluxed overnight. The solution is cooled to ambient temperature. and poured onto 500 g. of crushed ice. Ammonium sulfate (180 g.) is added and the solution continuously extracted with ether for several hours. The ethereal solution is evaporated to dryness to remove ether and acetic acid. and the residual oil dissolved in diethyl ether. washed with percent sodium carbonate solution. dried. and evaporated. The resulting oil is fractionated to give 8.96 g. (64 percent) of 3-oxo-3.4-dihydro-ZH-1.S-hcnzodioxcpin. b.p. 5Z 61 C. at 0.07 mm pressure. which at first is a col orlcss oil which solidifies. The product is used directly in the next step. Step D: Preparation of3-hydroxy-3-cyano-3.4-dihydro- 2H- 1 .5-benzodioxepin A solution of 13.5 g. (208 millimoles) of potassium cyanide in 27 ml. of water is added dropwise to a mixture of 18.7 g. (114 millimoles) of 3-oxo-3.4-dihydro ZH-1.5-benzodioxepin and 21.2 g. (208 millimoles) of acetic anhydride with stirring and cooling. The mixture is stirred at ambient temperature overnight and then is made alkaline with 1() percent sodium carbonate solu- Analysis calculated for .H NO

C. 62 1'41. H. 4 74; N. 7.33.

Found C. h: 71). H. 4 52.18.74).

An alternative method for preparing 3-hydroxy-3- cyano-3.4 dihydro-ZH-1.5-benzodioxepin can be carried out in the following manner.

To a stirred solution of 4.92 g. (30 millimoles) of 3- oxo3.4dihydro-ZH-1.5-benzodioxepin in 100 m1. of benzene is added dropwise a solution of 30 millimoles of anhydrous hydrogen cyanide in 51) ml. of benzene. The reaction mixture is stirred overnight at ambient temperature. basificd with 10 percent sodium carbonate solution and the organic layer separated. The ben zene solution is washed once with water and dried success'oely over anhydrous magnesium sulfate and calcium sulfate. Evaporation of the solvent under reduced pressure at 40 C yields the crude cyanohydrin in which upon purification and mixed melting point determination gives no depression with an authentic sample of 3-hydroxy 3cyano3.4-dihydro-2H- l .5- benzodioxepin.

Step EL Preparation of 3hydroxy-3-aminomcthyl-3.4- dihydro-ZHd .S-benzodioxcpin hydrochloride A mixture of9.5 g. (49.7 millimoles) of 3 hydroxy-3- cyano-3.4-dihydro-ZH-1.5-ben/odioxepin. 75 ml. of

anhydrous ethanol. and 3 ml. of acetic acid is shaken under hydrogen at ambient temperature and pressure in the presence of 100 mg. ofplatinum oxide and a little ethanolic-hydrogen chloride. The catalyst is removed and the filtrate evaporated to dryness to give 5.2 g. of crude product. m.p. 2U7214 C. Recrystallization of this crude product from isopropanol afford 3-hydroxy- 3-arninomethyl-3.4-dihydro-2H1.5-benzodioxepin hy' drochloride. m.p. 228-230 C. (clearing at 238 C.)

Analysis calculated for C ,H ;,NO;;.HCI:

C. 51.84, H. 6.09; N. (Lilo.

Found: C. 52.11, H. 6.13; N. 5.86.

An alternative method for preparing 3-hydroxy-3 aminomethyl-3.4-dihydro-2H-1.S-benzodioxepin can be carried out in the following manner.

3-Hydroxy-3-cyano-3.4-dihydro-2H-1.5- benzodioxepin (30 millimoles) is dissolved in 100 ml of dry diethyl ether and the solution added dropwise during a period of 0.75 hours under dry nitrogen to a stirred slurry of 3.8 g. (100 millimoles) of lithium aluminum hydride in 100 m1. of dry ether. The mixture is stirred under reflux for 2.25 hours and treated carefully with 3.8 ml. of water. An easily-filterable precipitate of metallic compounds is obtained by the dropwise addition of 5.7 ml. of 10 percent sodium hydroxide solution followed by 11.4 ml. of water. The ethereal solution is filtered and the filter-cake then is washed with 50 ml. of diethyl ether. The combined filtrate is dried over anhydrous magnesium sulfate and again over calcium sulfate before evaporation in a rotary film-evaporator to yield 5.13 g. (87 percent) of the free base as a colorless solid. m.p. 6063 C. (to a turbid melt). This product. upon recrystallization from benzene from which it separates as colorless plates melts at 66-68 C. A solution of 3.0 g. of the base dissolved in dry diethyl ether is treated with a slight excess of approximately SN ethanolic-hydrogen chloride solution affording 2.82 g. of 3-hydroxy-3aminomethy1-3.4-dihydro-2H-1.5- benzodioxepin hydrochloride. This product gives no depression in melting point when admixed with authen tic material prepared by the catalytic reduction of the cyanohydrin, as described above.

Step F: Preparation of 3-hydroxy3- isopropylaminomethyl-3,4-dihydro-2H-1.5- benzodioxepin hydrochloride A mixture of3.92 g. 16.95 millimoles) of 3-hydroxy 3-aminomethyl-3.4-dihydro-2H-1.ibenzodioxepin hydrochloride. 1.39 g. (16.95 millimoles) of anhydrous sodium acetate. and ml. of anhydrous ethanol is stirred under nitrogen for 20 minutes. Acetone (1.08 g.. 18.6 millimoles) is added and the mixture stirred for 30 minutes. The mixture is hydrogenated at ambient temperature and pressure for 1V2 hours over mg. of platinum oxide. The catalyst is removed. the solution evaporated to a syrup. 60 m1. of dry diethyl ether added. and a slight excess of 9.7N ethanolic-hydrogen chloride solution added. The solids are collected to give 4.65 g. of crude product. m.p. 172175 C. The product is recrystallized from isopropanol to give 3.05 g. (65 percent) of 3hydroxy-3-isopropylaminomethyl- 3.4-dihydro-2H-1.5-henzodioxepin hydrochloride. m.p. l78.518(l.0 C.

Analysts calculated for LMH NO HCI.

C. 57 ()4; H. 73b: N. 5.11. Found: C. 56.95. H. 7.19; N. 4.89.

An alternative method for preparing the benzodioxe pin of Step F can be carried out in the following manner.

3 Hydroxy 3-aminomethyl-3.4-dihydro-2H- l .5- benzodioxepin (I95 mg.. l millimole) is dissolved in isopropanol (3 ml.) and treated with acetone (64 mg. 1.1 millimoles). ()n standing overnight. the solution de posits a crystalline solid (glistening plates). and this is reduced in situ by the addition of sodium borohydride (756 mg. 2 millimoles). After stirring the mixture at ambient temperature for 3 hours water (20 ml.) is added and then 2.75M hydrochloric acid 1.5 ml. The solution is extracted with ether 10 ml.) and the extract rejected. Glycerol (l ml.) is added and the solution then is basified with 2N sodium hydroxide ml.) to liberate the free base. The latter is extracted with ether (25 ml. the ethereal solution washed with water (2 X ml.) and then dried thoroughly over magnesium sulphate followed by calcium sulphate. Addition of 5N ethanolic hydrogen chloride solution to the solution of base precipitate the 3-hydroxy-3- isopropylaminomethyl-3.4-dihydro-2H- l .5- benzodioxepin hydrochloride l 36 mg. 49.6 percent). No depression of melting point is observed when the product is admixed with an authentic specimen of the compound.

EXAMPLE 2 3-Hydroxy-3guanidinomethyl-Il,4-dihydro-2H-l .5 benzodioxepin sulfate 3Hydroxy-3-aminomethyl-3,4-dihydro-2H- l .5- benzodioxepin from Example 1. Step E. (l.95 g.. It) millimoles) and 2.78 g. (10 millimoles) of S- mcthylisothiourea sulfate in l5 mls. of dimethylformamide and 2 mls. of water is heated at MW-100 C. for 5 hours. The solvent is evaporated in vacuo and the residue recrystallized from ethanol to give 3-hydroxy-3- guanidinomethylfl .4-dihydro-2H- l .5-bcnzodioxcpin sulfate.

EXAMPLE 3 3Hydroxy-3-( 3-phenylguanidinomethyl )-3.4-dihydro- 2H-l .5-benzodioxepin hydriodide A mixture of S-methyl-N-phenylisothiourea hydriodide (2.94 g. [0 millimoles). 3hydroxy-3- aminomethyl-3.4-dihydro-2H-l,S-benzodioxepin 1.95 g. (It) millimoles) from Example 1. Step E. and mls. of ethanol is warmed until evolution of methyl mercaptan ceases and then is refluxed for 2 hours. The solution then is evaporated to a small volume and diluted with ether to give 3-hydroxy-3-( 3-phenylguanidinyl)- methyl 3.4-dihydro-2H-l.5-benzodioxepin hydriodide.

EXAMPLE 4 EXAMPLE 5 3-Hydroxy-3-l 2-phenylcyclohexyl )aminomethyl l-3.4- dihydro-2H- l .5-bcnzodioxepin hydrochloride By replacing the acetone employed in Example l.

Step F (or alternate Step F) by an equivalent quantity of Z-phenylcyclohexanone and then following essentially the same procedures described therein. there is obtained 3-hydroxy-3-I 2- phenylcyclohexyl)aminomethyl |3.4-dihydro 2H- l .5- benzodioxepin hydrochloride. nip. 2l3.52l5 (T EXAMPLE 6 3-Hydroxy-3- 2-( 3-cylcohexyl )propyl Iaminomethyll- 3.4-dihydro-2H-l.5-benzodioxepin hydrochloride By replacing the acetone employed in Example lv Step F (or alternate Step F) by an equivalent quantity of cyclohexylacetone and then following essentially the same procedure described therein. there is obtained 3- hydroxy-3-{[2-(3-cyclohexyllpropyl|aminomethyl}- 3.4-dihydro-2H-l.S-benzodioxepin hydrochloride.

EXAMPLE 7 3-Hydroxy-3-dimethylaminomethyl-3.4-dihydro-2H- 1.5-benzodioxepin hydrochloride 3-Hydroxy-3-aminomethyl-3,4-dihydro-2H- l .5- benzodioxepin (3.2 g.. 0.0l64 mole) from Example I, Step E. is added to formic acid (4.3 g.. 0.082 mole).

, Formalin (3 ml.) is added and the solution then heated on a steam bath for [7 hours. The yellow liquid is stripped. basified with 20 percent sodium hydroxide (l0 ml.) and twice extracted with ether ml. The ether extracts are combined and washed with water. then dried over magnesium sulfate and calcium sulfate then evaporated yielding 3.4 g. of an oil which upon acidification with cthanolic-hydrogen chloride crystal lizes as the hydrochloride melting at l l8-l 20 C.

EXAMPLE 8 3-Hydroxy-3-methylaminomcthyl3.4dihydro 2H- l .5- benzodioxepin hydrochloride Step A: Preparation of 3-hydroxy3-formamidomethyl- 3.4-dihydro-2H-l.S-benzodioxepin A mixture of I49 g. of 97 percent formic acid and 3.21 g. of acetic anhydride is heated in a water bath for 2 hours (internal temperature did not exceed C.) then cooled and added dropwise to a slurry of 5.86 g. of 3-hydroxy-3-aminomethyl-3.4dihydro2H-1,5-

benzodioxepin from Example 1. Step in ml. anhydrous ether. A gummy white solid forms which slowly dissolves with stirring at ambient temperature overnight. The clear liquid obtained is washed twice with water. twice with ll) percent sodium carbonate and twice with water. The ether then is evaporated affording 2.5 g. of semi-solid material.

An oil, insoluble in either water or ether. is collected with the water and then removed by shaking the mixture with chloroform. Upon stripping the chloroform layer there is obtained 3.6 g. of 3hydroxy3 formamidomethyl-3,4-dihydro-2H- l .5-benzodioxepin in the form of a semi'solid.

Step B: Preparation of mcthylaminomethylJ.4-dihydro-2H l ,5- benzodioxcpin hydrochloride 3-Hydroxy 3-formamidomethyl-3.4-dihydro-2H- l .5 benzodioxcpin (5.8 g.) in 2(lt) ml. anhydrous ether is added to lithium aluminum hydride (2.0 g.) in 40 ml. of anhydrous ether dropwise in 1 hour. The mixture then is refluxed for 2 hours and the lithium then decomposed with water (5.0 ml.) followed by ll) percent sodium hydroxide (3.6 ml.) followed by 6.0 ml. of wa- 3-hydroxy-3- ter. The white solid formed is filtered and the filtrate dried over magnesium sulfate then over calcium stiltiite. It is stripped affording 3.8 g. of oil. The oil is ucidioxepins I having the R substituent specified in Table tied with l lN hydrochloric acid in ethanol to give 3.7 l-

H TABLE I H 011 H OH 4- Carbonyl Reactant mste F O HzNHFHCl Method I IIDH H H III" Ex. Carbonyl Empirical m.p. Analysis No. Rcactant R Formula C. C H Cl N P v 9 :.-C=o -CH(CH (c 11 c .,i1 No -11e1 183-184 Calc. 56.43 7.71 12.32 4.87 Found 58 .66 7.66 1.2.55 4 .83 c11 ElO-@CH C=O -c11 (c11 -CH OH e 11 110. -6 1 o.127-129 Calc. 3.28 7.25 Found 3.28 7.38

11 -ces-c-o -c11(c11 )-c11 w C H N OyHCl 190-191 CalC. 64.06 6.48 9.12 7.20

(dGC-) Found 64.55 6.46 9.25 7.13

9 12 c1-@-c!-1 c=o -CH(CH3)-CH27 e 11 c11-10 11c1 163- CEllC. 59.39 6.03 18.45 3.64 165 Found 59.56 6.15 18 3.83 01 c11 11 @-(CH1)2-C=O -c11 c11 )-(c11 1, C20H25NO3HC]. 180-183 CalC. 66.02 7.20 9.74 3.85 FDUnd 66.12 7.12 9.65 3.91

1-1 Cll.-C.O 4 11, C Il NO- HCl 1.81.5- CalC. 55.49 6.99 13.65 5.39 1.83 FOtl'id 55.72 6.73 13.49 5.49

15 -CI.U -c11 C il NO -llCl 214-216 CEilC. 63.45 6.26 11.02 4.35 Found 63.62 6.39 10.09 4.37

16 @cg-cno c11,1 C H NOyllCl 229-231 CalC. 64.38 6.60 10.56 4.17 Found 64.39 6.27 10.74 4.23

17- CEi 1l-O 4110311 11211 c .,11; No.-1ic1 170-174 0616. 65.23 6.91 10.13 4.00 Found 65.59 6.69 10.20 4.14

fi Cll(CH )CH C ll NO -HCl 188-189.5Calc. 60.00 6.14 9.00 3.56 18 1 CH3 F6666 61.02 6.14 8.91 3.30

out. 14 3 c u uo flicl 220- C1310. 60.06 6.87 8.06 3.18

u 221 5 Found 24 6 91 7 96 3 O9 u n 112-114 c616. 66.46 6.16 4.03 Found 66.56 6.14 3.65

g. of B-hydroxy-3-methylaminomethyl-3.4-dihydro-ZH- Table ll also describes additional products made by 1.5-benzodioxepin hydrochloride, m.p. l89205 C. the procedure of Example l. The products identified Following several recrystallliyaitions from ethanol. the here lll't. prepared by replacing the catechol employed product melts at 2l72l9. C. in Step A of Example I by an equimolecular quantity Other benzodioxepins prepared by the methods deof the catechol E halving the R and R substituents scribed in Example 1 are identified in Table l. in panic given in the table which then is carried through the pro- UlZlf the ketone. acetone. employed in Step F of Exumcedures described in Steps A-E of Example 1 to prople l is replaced by the carbonyl compound identified vide the 3-hydroxy-3-;1minomethyl compound D. Comin the following table. which. following substantially pound D thus obtained upon reaction with acetone acthe same procedure there described. gives the benzodicording to the procedure described in Step F of Exampic I proyides the 3.3-disubstituted-benzodioxepin l haning the substituents R and R given in Table ll.

as described in Step E of Example 1. there is obtained 3-( l-aminocthyl )-3-hydroxy-3,4-dihydro-ZH- I .5-

TABLE II it i H a on O OH Exam 1e 1 Ste F Lxampltztlditeps A 23 Metllw P R CHZNHCMCM) A on 1 0 m nn -cl O R H H R ll ll "E" IIDH "In Example Empieical m.p. Analysis 110. R R Formula c. c It Cl N m H CH3 C d NOyHCl l75-l77 Calc. 58.42 7.71 12.32 4.87 y Found 58.66 7.70 12 5.00

21 1] cl C H ClNOyI-KCI 17l- Calc. 50.66 6.21 33.01 4.54 172.5 Found 50.49 6.17 23.15 4.b9

. 65 22 -0ca a c fl uot. e uip 155 157 Calc. 56.39 6.57 3.

l Found 56.38 6.51 3.97

The preparation of the benzodioxepin bearing an R" substituent by the reaction of the 3-keto intermediate A with a nitro-alkane thus following the route A B H D e l is illustrated by the examples below. It will be understood that other nitroalkanes and other 3oxo-lienzodioxepins can be employed as starting materials as well as other aldehydes or ketones of the type described as suitable above. it also is possible to employ the nitro-alkane in the route A B D E I shown in Flow Diagram l.

EXAMPLE 23 3-Hydroxy-3-t l-isopropylaminoethyl)3.-l-dihydro- ZH- l .5-benzodioxepin hydrochloride Step A: Preparation of 3-hydroxy-34 l-nitroethyl)-3.4- dihydro-ZH- l .S-benzodioxepin To a solution of 3-oxo-3,4dihydro 2H- l ,5- benzodioxepin (9.84 g. 60 millimolcs) prepared as de scribed in Example l. Steps A-C in anhydrous ethanol ml.) is added nitro ethane It) ml. and the mixture cooled to (l-5C. A solution of sodium g.. 65 millimolcs) in anhydrous ethanol (30 ml.) then is added dropwise with stirring at about 5 C. Stirring is continued at this temperature for 1 hour and for another hour at ambient temperature. Dry ether (60 ml.) is added and the mixture then stirred overnight. More dry ether (60 ml.) is added and the solid is collected after stirring the mixture for 2 hours to give 5.73 g. of product after drying in a desiccator.

Evaporation of the mother liquors to a syrup and di lution with dry ether (ca. ml.) yielded a further 5.32 g. of product.

Treatment of a suspension of the combined yield of product in dry ether with a slight excess of acetic acid liberated 3-hydroxy-3-tl nitroethyl)-3.4-dihydro-2H- l.5ben7.odioxcpin which is isolated from the ethereal solution after washing the latter with water and then drying it thoroughly first over magnesium sulfate and then over calcium sulfate.

Step B: Preparation of 3 laminoethyl)-3-hydroxy- 3.4-dihydro-2H- l .S-benzodioxepin hydrochloride The crude nitro compound (5.34 g.. 22.3 millimolcs) dissolved in a mixture of ethanol (30 ml.) and acetic acid (2 ml.) is hydrogenated at 45 C. and atmospheric pressure in the presence of Raney nickel (ca. 2.5 g.)

On working up the product as its hydrogen chloride salt bcnzodioxepin hydrochloride. mp l78-ll-'3 C. after crystallization from a mixture of isopropanol and ether.

Step C: Preparation of 3-hydroxy-3'l l isopropylaminoethyl l-3 .4-dihydro-3H l .5- henzodioxepin hydrochloride By replacing the 3hydro\y3-aminomethyl-3.4- dihydro-ZHJ.5-hen/odioxepin hydrochloride employed in Step F of Example I by an equivalent quantity of 3-hydroxy-3-t laiminoethyl)JAdihydro-ZH- l.5-bcnzodioxepin hydrochloride and employing the same reaction conditions called for in Example 1. Step F. there is obtained 3-hydroxy-3-( lisopropylaminoethyl )JA-dihydrofl H- l .5- henzodioxepin hydrochloride, mp. ION-2| l C. It was purified by recrystallimtion from ethanol giving a product of m.p. 2l57 EXAMPLE Z4 3-Hydroxy-3I l-( isopropylamino )propyl I-BA-dihydro- 2 H-l ,S-benzodioxepin hydrochloride Step A: preparation of 3-hydroxy 3-( l-aminopropyl)- 3,4-dihydro-2H- l .5ben7odioxepin hydrochloride By following the procedures described in Steps A and B of Example 23. but replacing the nitroethane by an equivalent quantity of l-nitropropanc. there is ob tained 3-hydroxy3-(l-aminopropyl)-3.4-dihydro lH l.5-benzodioxepin hydrochloride. mp. [QT-I98 C. after crystallization from isopropanol.

Analysis calculated for .H N() .H(l:

C. 55.49: H. 6.99. (L 13.65; N. 5.39;

Found: C. 55.28; H, 7H4, CI. 13.9). N. 5.57.

Step B: Preparation of 3-hydroxy-3-l l- (isopropylamino )propyl ]-3,4-dihydro-2H- l .5- benzodioxepin hydrochloride This product is prepared by the procedure described in Example I Step F except the 3-hydroxy-3- aminomethyl-3.4-dihydro2H-lt5-benzodioxepin employed therein is replaced by an equivalent quantity of 20 3-hydroxy-3-( l-aminopropyl )-3,4-dihydro-2H-l ,5- benzodioxepin.

By following the procedure called for in Example 23, Step C, but employing the carbonyl reactant identified in Table III, there are obtained additional products I having an R substitutent. Illustrative examples are provided in the following Table.

u TABLE 111 a H OH on 0 o H-NH -HCl Carbonyl Reactant Exam le 1, Ste F 0 {In Method 9 0 a a H "D" III Example Intermediate Nu. from Example R Carbonyl Reactant R I 25 23 -cn C2H5-C=O -cu(en (C2H5) 26 23 -c1: 3 -cn;-c=o -c1 1 (CH3) CH2 @N' [NQ 27 24 -cu ca I -ca -c=o -cH(cH )-cu -ij N IN I 28 23 -cu H0-CH2C=O -cn (c11 -cu --OH '7 I c9 24 cn ca HO-QCHQC o cu(c,la) chz @4311 30 23 -CH3 H3 cfirc=o CH(CH3)CH2- I 31 23 -ca; Cl ci: -c=o -CH(CH3)-CH2CIL I 32 24 -CH2CH3 @CH2C=0 -catca )cu 33 23 -c1-1 cn -cuo -(ca 34 23 -ca en -c110 -c n 35 23 -cn S-cao CH'/ 9 36 24 CH2CH3 Q Z =O CH(CH lCH -O C} 2-O \0C}H2 cn ca 37 23 -cn 3 3 CHEW Q -cn(ca )-ca -oca 0on c11 a 3 CH[CH3)(CH2)2 38 24 -CH2CH3 (CH2)2-C=O 39 24 :a ca CH3-CHO C2H5 TABLE III (Contd.)

"D" Example Intermediate No. from Example R Carbonyl Reactant R Additional illustrative examples of products made by -cn (c11 -cu Example 23 procedure are provided in Table [V OCH;

.-y., t L

Ex. Inte mediate tlo. tram ilxarple R R1 R" Carbonyl Rcactant RE C|tt at ..z -eii, i: ca teii Q tciio ,-e:o CH(CIt (CHA) n4 tl e1 -cu. Cu -cuo C; H

55 21 a ct -eii Q-cuo -ca 5o 21 It cl cu; @cu -ciio -tCH The following examples illustrate the preparation of the 3.3-disubstituted-benrodioxepins l by forming the 3spiro-2'-oxirane which when reacted with an amine gives the desired product I. that is the route I) F. I illustrated in Flow Diagram I it will be appreciated that anyone of the intermediate compounds D dcscribed in this disclosure as well us others falling within the scope of its definition can be employed as starting substance and an amine of structure HNRR can be substituted for the particular antine employed to pro \iLiC the desired product 1.

EXAMPLE 5? Step A: Preparation of 3.4-dihydro-2H- t .5 benlodioxepinJ-spiro-2'-oxirane A solution of sodium nitrite ((19 g; tl.l mole) in water 5t) ml. t is added slowly over a period ofone-half hour with stirring to a solution of 3-hydroxy-3- aminomethylfl.4-dihydro-2H-l.5-benzodioxepin h drochloride (23W g; til mole). in water (200 ml.| containing acetic acid ((Ll ml.) while maintaining the reaction mixture at a temperature between about 4 to 0C When the addition is completed the reaction mixture then is allowed to warm to ambient temperature, The solid that forms is collected and washed with a little water to yield l-HM g. of crude product. m.pi l32l44 C. Following recrystallization from methanol (approximately 3t) parts \"lWt there is obtained H115 g. .93 percent! of 3.4-dih 'dro-2H-l.5- benzodioxepin-F-spiroI-o\irane. mp, l4 l49 Analxsts calculated for H S (I n? 4o. H. 5 t). limit Found. (17' 4h. H. 5 4h. U. 3T

Recrystalliration ofthe crude product ofStep A from chloroform also provides purified product that does not depress the melting point when taken in admixture with the purified product of Step A.

The mother liquor remaining after the removal of the crude product in Step A is extracted with ether yielding an oil I g.) which crystalliyes from carbon tetrachloride to afford 3tlt) mgst of 3-hydro\ \J-hydroxyntethyl- 3.4-dihydro-2H-l.S-benzodioxepin. m.p. l2lll23 C. Recrystallization of the diol from water ((1 roll provides Z54 mgs. of product, m.p. [24.5 1255 (T Ill Analysis calculated for H O (f. bl Ill H. 6.17;

Found. (f. (it lo; H. 6.28.

The diol obtained as described above also exhibits B-adrenergic stimulating properties and therefore is useful as a bronchial dilating agent.

Step B: Preparation of 3-hydroxy-3-t. bu tylaminomethyl-3.4-dihydro-2H-l .S-benzodioxepin hydrochloride The 3.4-dihydro-2Hl.S-benzodioxepin-3spiro 2- oxirane L78 g. I. obtained as described in STep A. is stirred at ambient temperature with t.-butylamine (3.2 ml,) in methanol (25 ml.) for 42 hours, The solution then is evaporated to 2.6 g. of oil which is separated and dissolved in ether and then acidified with 1 IN HCI in ethanol (2.5 ml.) to give 2.0 g. of crude product, mp. lhJ.5-177 C, After recrystallization from isopropanoi containing decolorizing charcoal there is ob- 3Hydrox '-3-( Z-dimethylaminoethyl )aminomethyl- 3 .J-dihydro-ZH- l ,S-benzodioxepin dihydroehloride 3.4-Dihydro-2Hl .5-benzodioxepin-3-spiro-2 oxirane (3.50 g. It] millimoles) from Example 57. Step A. is stirred with 5.3 g, millimolesl of unsymmetrical dimethylethylenediamine in 50 m]. of methanol for 48 hours at 3tl4t) C The solution is evaporated to remUYC methanol and excess dimethylethylcnediamine.

The residual oil is dissolved in diethyl ether and aciditied with ethanolic-hydrogen chloride to give crude product hydrochloride, This product is dissolved in ethanol. treated with charcoal. and filtered. Concentration of the filtrate and refrigeration affords B-hydroxy-B-U- dimethylaminoethyliaminomethyl-3.4-dihydro-2H- lfi-benzodioxepm dihydroehloride.

The following example describes the preparation of the 3-spiro-Zoxirane E from a 3-oxoben2odioxepin A employing a sulfur ylide. While the example describes EXAMPLE 3.4-Dihydro-2H- l .5-ben2odioxepin-3-spiro-Z '-oxirane 3-Oxo-3.4-dihydro-ZHl.5-benzodioxepin (L64 g.'.

millimoles) from Example 1. Step C. is added slowly 10 with stirring during l5 minutes at ambient temperature to a solution of dimethyloxosulfonium methylide prepared under nitrogen from millimoles ol'sodium hydride. l5 millimoles of trimethyloxosulfonium iodide.

and mls. of dimethyl sulfoxide. The mixture is 15 stirred for 24 hours at ambient temperature and then 2 hours at -50 C. The mixture is cooled and poured onto g. of ice and repeatedly extracted with diethyl ether. The ethereal extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product is crystallized from methanol to afford the 3.4-dihydro-2H- I .5-ben2odioxepin-3-spiro-Z- oxirane identical with the product prepared from 3- hydroxy-3-aminomethyl-3.4-dihyd ro-2H- l .5- benzodioxepin as described in Example 57. Step A.

The other 3-oxo-3.4-dihydro-2H-l.S-benzodioxcpins described specifically in this disclosure or falling within the scope of the definition of the 3-keto compound A can be substituted for the particular 3-keto starting substance in Example 59 to provide the desired 3-spiro- 2'-oxirane of structure E.

Additional compounds prepared by the process de scribed in Example 57 are identified in Table V. The products of Table V are prepared by replacing the t.- butylamine employed in Step B of Example 57 by an cquimolecular quantity of the amine having the structure HNR R identified in Table V and then following substantially the same procedure described in Step B.

TABLE v H H 8 a ll 0 0 0 O 5 6 Exam 1e 57 Ste B 5 0 @[o HNR R g 11 ml R Example Empirical m Analysis No. NR5R5 Formula C 11 Cl N cn l c 8 -nc1 187-189 Calc. 57.46 6.68 13 .05 5. 15 C1 2 Found 57 .39 6.76 12 .78 5.27

51 -nu-c (Cll C5CH 0 8 80 -1101 190.5- Cale. 60.50 6 .77 11 .91 4 .70 192.5 Found 60.25 6 .86 12.04 4 .88

62 -n H 0 c L.8 110., -uc1 173-176 Cale. 55.72 6 .68 11.75 4 .64 Found 55.60 6 .85 11.61 4 .78

63 -nn-e (c11 -en ion c 11 ,no c nto. 138.5- Cnlc. 56.39 6.57 3 .65 Found 56.48 6.78 3 77 64 N H N@ O c u a 127-128 CalC 70 57 7 11 8 21 20 24 2 s Found 70 .81 7 44 7 .88

65 -N|I C l1 1 l O Calc. N Found 66 aux-Q c 0 7N 0 -1401 267-276 Calc. 65.65 7.71 9.69 3.83 Found 66.04 7.87 9.86 4 .09

67 NH- (c14 -0- c11 -ou c u n OgHCl 157- Calc. 52.58 6.93 11.09 4.38 158 .5 Found 52.26 6.53 11.42 4. 39

68 -an- (CH2) -n H o c 8 11 0.. '2HC1 270-281 Calc. 51.65 7.14 17.94 7.09 Found 51 .88 7 52 17.64 6 .85

69 -NH-CH -CHOI l-CH c u n o s-c a o 177- Cale. 46.05 4 .77 9 .48 7 .23 Found 46.18 5.10 9 .53 7.52 s

70 NH@ 0 Eli] 7N o -8c1 -195 Calc. 62 .44 5.89 11 .52 4 55 Found 62.40 5.99 11 .75 4.37

11 O G) 71 :n (CH2) aa-clay C H N O '2HCl 274-277 Calc. 57.25 7 .02 13.00 5.14 0 Found 57.15 7.02 13.26 5.32

72 -NHCH2CH(OH]- c li no -ucl 200-202 Calc. 61.45 6.3-? 10.08 3.98 Found 61.65 6.50 10.32 3.90

G) 2 mole of epoxide to 1 mole of the diamine employed in synthesis.

run v {cgrd] ml. Empirical mp.

lo. -Ill Iomull c. c 11 c1 n s 12-. -II -I1 2xJ.5-2.s.o Cale. 67.77

Additional 3.3-disubslituted-benzodioxepins made 15 by the reaction of 3.4-dihydro-2H-l ,S-benzodioxepin- D HNRSRG B, are described in Table VI.

TABLE VI Example Method The following examples describe the preparation of certain 3.3-disuhstituted-benzodioxepins having at least one suhstituent attached to its benzenoid moiety.

EXAMPLE 85 3-Hydroxy-3-isopropylaminomethyl-7-nitro- 3 .4- dihydro-ZH- l .S-benzodioxepin Hydrochloride Step A: Preparation of 7-Nitro3.4-dihydro-2H-l.5- benzodioxepin-3-spiro-2'-oxirane A mixture of 0.11 mole of nitroniurn tetrafluoroborate and 60 g. tetramethylene sulfone is stirred at 10 C. and 0.1 mole of 3.4-dihydro-2H-l.5- benzodioxepin-3-spiro-2-oxirane. prepared as described in Example 57. Step A. added during minutcs. The cooling bath then is removed and the mixture stirred an additional 20 minutes at C. poured into ice and water. the product extracted with ether. the ether solution dried over magnesium sulfate and evaporated. The product obtained following crystallization from a mixture of chloroform and petroleum ether is 7-nitro-3.4-dihydro-2H- l .5-benzodioxepin-3-spiro-2 oxirane. Step B: Preparation of 3-hydroxy-3- isopropylaminomethyl-7-nitro 3.4dihydro-2H- l .5- Benzodioxepin Hydrochloride By replacing the 3-spiro-2'-oxirane and the t.- butylamine employed in Step B of Example 57 by equivalent quantities of 7-nitro-3.4-dihydro-2H-l.5- benzodioxepin-3-spiro-2-oxirane and isopropylamine respectively and then following substantially the same procedure there described. there is obtained 3- hydroxy-3-isopropylaminomethylJ-nitro-3.4-dihydro- ZH-LS-benzodioxepin hydrochloride.

EXAMPLE 86 S-Hydroxy-3-isopropylaminomethyl-7-amino-3.4- dihydro-ZH- l .5-benzodioxepin Hydrochloride Step A: Preparation of 3-Acetoxy-3( N- acetylisopropylaminomethyl)-7-nitro-3.4-dihydro-2H- l.5-benzodioxepin Treatment of 3-hydroxy lisopropylaminomethylJ- nitro-3.4-dihydro-2H-l.S-benzodioxepin. obtained as described in Example 85, with excess acetic anhydride and heating overnight on a water bath affords the 3- acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro- 3.4-dihydro-2H-l.S-benzodioxepin. Step B: Preparation of 3-Acetoxy 3-( N- acetylisopropylaminomethyl)7-amino-3.4dihydro- ZH-l .S-benzodioxepin The 3-aeetoxy-3-(N-acetylisopropylaminomethyl)7- nitro-3.4-dihydro 2H-l,5-benzodioxepin when dissolved in ethyl acetate is reduced at low pressure over platinum with hydrogen to give 3-acetoxy-3-(N- acetylisopropylaminomethyl)-7-amino-3.4-dihydro- ZH-LS-benzodioxepin. Step C: 3-Hydroxy-3-( isopropylaminomcthyl )-7- aminoBA-dihydroZH- l .S-benzodioxepin hydrochloride 3-Acetoxy-3-( N-acetylisopropylaminomethyl )-7- amino-3.4-dihydro-2H-l.5-bcnzodioxepin (33.6 g.. ().l mole) is refluxed for 10 hours with 400 ml. of methanol containing 20 g. (0.5 mole] of sodium hydroxide. The solvent is removed at low temperature in vacuo and the residue treated with 200 ml. of water. The mixture is extracted with diethyl ether and the combined ethanol phases washed with water and dried over anhydrous magnesium sulfate. The sohent is evaporated and the product. 3-hydroxy-3-(isopropylaminomethyl)-7 amino-3.4-dihydro-2-H-l.S-benzodioxepin hydrochloride isolated as the hydrochloride salt.

EXAMPLE 87 3-Hydroxy-3'isopropylam inomethylJ- methanesulfonamido-3.4-dihydro 2H- l .S- benzodioxepin Hydrochloride Step A: Preparation of 3Aeetoxy-3-( N- acetylisopropylaminomethyl)-7-methanesulfonamido- 3.4-dihydro-2H- l .S-benzodioxepin Methanesulfonyl chloride (().l mole) is added dropwise to a stirred solution of().l mole of 3-acetoxy-3 N- acetoxyisopropylaminomcthyl)-7-amino-3.4-dihydro- 2H-l.5-benzodioxepin. from Example 86. Step B. in I20 ml. of pyridine held at l()l5C. The mixture is stirred for several hours at ambient temperature. then heated to C. for 0.5 hours. cooled. and added to an ice-water mixture. The mixture is extracted with ether. washed. dried over magnesium sulfate. and the solvent removed to give 3-acetoxy-3-( N- acetylisopropylaminomethyll?-methanesulfonamido- 3.4dihydro-2H- l .S-benzodioxepin. Step B: Preparation of 3-Hydroxy-3- isopropylaminomethyl-7-methanesulfonamido-3.4- dihydro-ZH-l .S-benzodioxcpin 3-Acetoxy-3-( N-acetylisopropylaminomethyl )-7- methanesulfonamidod.4-dihydro-2H- l .5- benzodioxepin (4.2 g. It) millimolc] in 20 ml. mctha nol is treated with 2 g. (50 millimolcs) of sodium hydroxide in 20 ml. ofmethanol. The mixture is refluxed for three hours. cooled. and diluted with 400 mls. of water. neutralized with acid and extracted with ether. The combined ethereal solutions are washed with water. dried over anhydrous sodium sulfate. and evaporated to give B-hydroxy3-isopropylaminomethyl-7- methanesulfonamido-S.4-dihydro-2H- l .5- benzodioxepin.

EXAMPLE 88 3Hydroxy-3isopropylamino-7-carbethoxyamino-3.4- dihydro'ZH- l .5-bcn7odioxepin Step A: Preparation of 3-Aeetoxy-3(N- acetylisopropylaminomethyll-7-carbethoxyamino-3.4- dihydro-ZH-l.S-benzodioxepin 3-Acetoxy-3-N-acetylisopropylaminomcthyl-7- amino-3.4-dihydro-2H*l.S-benzodioxepin (().l mole) from Example 86. Step B. in chloroform is treated with ().l l mole ofethyl chloroformate and pyridine in chloroform. The mixture after stirring and heating in a water bath for several hours is diluted with water. ex tracted with ether. the combined ethereal extracts washed. dried and evaporated to give 3acetoxyJ-( N acetylisopropylaminomethyl)-7-carbethoxyaminn-3.4- dihydro2H- l .S-benzodioxepin. Step B: Preparation of 3Hydroxy-3- isopropylaminomethyl-7-carbethoxyamiota-3.4- dihydro-ZH- l .S-bcnzodioxepin 3-Acetoxy-3-( N-acetylisopropylaminomethyl )-7- carbethoxyamino-3.4-dihydro-2H-l.S-benzodioxcpin (4.l g. 10 millimoles) is warmed 5 hours at 40C. with 6 ml. of concentrated hydrochloric acid and 34 ml. of ethanol. The solution is cooled. taken to the basic side with sodium hydroxide. diluted with water. and ex tracted with diethyl ether to give 3-hydroxy-3- isopropylaminomcthyl-7-carbcthoxyamino-3.4- dihydro-2H-l .S-benzodioxepin.

EXAMPLE s9 3 .7 Dihydroxyd-isopropylaminomethylfi.4-dihydro- ZH- I .ibenlodioxepin 3 Acetoxy 34 N'acetylisopropylaminomethyl-7 amino-BA-dihydro-ZH- l .S-benzodioxepin from Exam ple so. Step B. dissolved in dilute sulfuric acid is treated with sodium nitrite in water and the mixture heated on a water bath for U hours. The mixture is cooled. neutrali/ed with base. extracted with ether, the ethereal extract washed. dried. and evaporated to give 3 7-dihydroxy-3-isopropylaminomethyl-3 4-dihydro- 2H- l .Sl CHIULllUXCPlH.

EXAMPLE Jtl 3-Hydroxy3-isopropylaminomethyl7methoxy-3.4 dihydro-ZH- l .5benzodioxepin 3.T-Dihydroxy-R-isopropylaminomcthylJ-.4-dihydro- ZH-lfi-benzodioxepin (2.53 g; ltl millimoles) from Example 8) dissolved in ml. of diethyl ether is left ltl hours at ambient temperature with 0.46 g. t l l millimoles) of dia/omcthane in 15 ml. of diethyl ether. Ex ccss diazomethanc is destroyed by addition of a few drops of acetic acid. The solution then is Washed with water. dried over anhydrous sodium sulfate. and evaporated to dryness to give 3-l'iydroxy-3- isopropylaminomethyl-Wmethoxy-3.4-dihydro-2H l .5 benzodioxepin.

The products of Examples through can also be prepared following substantially the same procedures described in these examples but instead of employing the 3spiro-2'-oxirane starting substance in Example 85. Step A. one uses an oxamlidinone which can he prepared from product I by treatment with dibutyl carbonate and metallic sodium or by treatment with phos gene The following example illustrates the preparation of the oxazolidinone and its use in preparing the desired 7substituted compounds of Examples 85 through 90.

EXAMPLE 9] 3-Hydroxy-3isopropylaminomethylJ-nitro3.4- dihydro-ZH- l ,S-benzodioxepin.

Step A: Preparation of 3 isopropyl-3.4-dihydro2H- l.ibenzodioxepinfi spiro-5 oxa7.olidinZ-one A mixture of B-hydroxy-3-isopropylaminornethyl- BA-dihydro-ZH-l.5benzodioxepin l I85 g.; 50 milli moles). prepared as described in Example 1. and dibutyl carbonate Ill g.) with a small piece of metallic sodium is heated in an oil bath. The temperature then is slowly raised to 170 C. with removal of butanol. Finally the mixture is heated between l7t]-20(l C. with removal of excess dibutyl carbonate. The cooled reaction product is dissolved in bemene. washed with water. dried over sodium sulfate, and the solvent evaporated to give 3 -isopropyl-3.4-dihydro 2H l .5- benzodioxepin3-spiro5-oxazolidin-2'-one. m.pv lil -132 C. Step B: Preparation of 3'isopropyl-7-nitro-3A dihydroQH- I ,5-benzodioxepin-3-spiro-5' oxazolidin 2-one By replacing the 3.4-dihydro-2H-l.Sbenzodioxepin 3spiro'Z-oxirane employed in Example 85. Step A. by an equivalent amount of 3'-isopropyl-3,4-dihydro-ZH- l.5ben2odioxepirrLspiro-S '-oxa7olidin-2-one and following substantially the same procedure there described. there is obtained 3'-isopropyl-7nitro-3.4- dihydro-ZHl .5benzodioxepin-3-spiro-5 -oxa2olidin- Z'-one. m.p. l45.5l47 C,

Step Preparation of 3-hydroxy-3 isopropylaminomethyl-7nitro-3,4-dihydro 2H- l .5 henzodioxepin A mixture of (H5 mole of the oxaYolidinone from Step B above and 15 g. ((1.38 mole) of sodium hydroxide in ml. of water and Zt'ltl ml. of 5 percent etha nol is refluxed. the solution evaporated to a small volume and the product extracted with diethyl ether. Evaporation of the solvent gives 3-hydroxy3 isopropylaminomethylJ'-nitro-3.4-dihydro-ZHl ,5- benzodioxepin.

Example 92 3-Hydroxy-3-isopropylaminomethyl-V- methanesulfonamidt)-3,4dihydro-2H l .5-

benzodioxepin Step A: Preparation of 3'-isopropyl-7-amino 3.4- dihydroQH-l,S-benzodioxepin-3-spiro-5'-oxazolidin- .T-onc By replacing the 3acetoxy-3-N- acetylisopropylaminon1ethyl-7-nitro-3,4'dihydro-2H- 1.5benzodioxepin used in Example 86, Step B, by an equivalent quantity of 3"isopropyl-7-nitro-3,4- dihydro-ZH-l ,5-ben2odioxepin-3-spiro-5 '-oxazolidin- 2-one obtained as described in Example 9i, Step B and then following substantially the procedure described in Example 86. Step 8. there is obtained 3- isopropyl-"i-amino-3.4-dihydro-2H-lfi-benzodioxepin- 3-spiro5'-oxazolidin-2'-one, Step B: Preparation of 3'-isopropyl-7- methanesulfonamido3.4-dihydro-2H-1.5- benzodioxepin-3-spir0-5-oxazolidin-2'-one By reacting the oxazolidinone obtained in Step A with methanesulfonyl chloride and employing the other reaction conditions and procedure described in Example 87. Step A. there is obtained 3-isopropyl-7- methanesulfonamido-3,4-dihydro-2H-l.5- benzodioxepin-3-spiro-5'-oxazolidin-2'-one. Step C: Preparation of 3-hydroxy-3- isopropylaminomethyl7-methanesulfonamido-3.4- dihydro-BH-l.5-benzodioxepin This product is prepared by substituting the oxazolidinone compound of Step B above for that employed in Example 9|. Step C. and following essentially the same reaction there described.

Example )3 3-Hydroxy-3isopropylaminomethyl-7- carbcthoxyamino-3,4-dihydro-ZH- l .Sbenzodioxepin Step A: Preparation of 3'-isopropyl-7- ethoxycarbonylamino-3.4-dihydro-ZH-l ,5- benzodioxepin'3spiro-5'-oxa2olidin-1'-one By replacing the 3-acetoxy-3N- acetylisopropylamino-7-amino-3.4dihydru-ZH-[,5- benzodioxepin reactant in Example 88. Step A. by the 3'-isopropyl-7amino-3.4-dihydro 2Hl,5- benzodioxepin-B-spiro-5'-oxaZolidin-2'-one. prepared as described in Example 92, Step A. and then following substantially the same procedure described in Example 88. Step A there is obtained 3'-isopropyl-7 carbethoxyaminofi.4-dihydro 2H-l.5-ben2odioxepin- 3spiro5'-oxazolidin' one.

Step 8: Preparation of 3-hydroxy-3 isopropylaminomethyl-7-carbethoxyamino-R,4- dihydro-2H- l .S-benzodioxepin The oxa7olidinonc from Step A above is refluxed in ethanol containing anhydrous hydrogen chloride. The solution is neutralized. evaporated to a small volume. diluted with water and extracted with ether. The dried ethereal solution is evaporated to give the desired product Example 94 3.7-Dihydroxy-3-isopropylaminomethyl-3.4-dihydro- 2H- l .S-benzodioxepin Step A: Preparation of 3'-isopropyl-7-hydroxy-3.4- dihydr-2H-l.5-benzodioxepinJ-spiro-S'-oxazolidin 2'-one This product is prepared by following the procedure and employing the reactants and reaction conditions described in Example 89 except the 3acetoxy-3-N- acetylisopropylaminomethyl-7-amino-3.4-dihydro-2H- 1.5-benzodioxepin there employed is replaced by the oxazolidinone obtained as described in Example 92. Step A. Step B: Preparation of 3.7-dihydroxy-3- isopropylaminomethyl-B.4-dihydro-2H- l .5- benzodioxepin This product is prepared by substituting the oxazolidinone compound of Step A above for that employed in Example 9l. Step C, and following essentially the same reaction there described.

Example 95 3 Hydroxy-3-isopropylaminometh yl-7-methoxy-3 ,4- dihydro-2H l ,5-ben2odioxepin Example 96 3 .(i-Dihydroxy-3-isopropylaminomethyl-3 .4-dihydro- 2 H-l .S-bcnzodioxepin Hydrochloride Step A: Preparation of2-methoxy-2-methyl-4-hydroxyl.3-benzodioxolc A mixture of pyrogallol (25.2 g. 0.2 mole) and trimethyl orthoacctate (26.4 g. 0.22 mole) is treated with one drop of concentrated sulfuric acid and the reaction mixture then stirred under nitrogen in an oil bath at l()3l05 C. Methanol formed in the reaction is distilled up a short column and collected. After 1 hour. more trimcthyl orthoaectate (2 g. 0.0 l 6 mole) and another drop of sulfuric acid are added and the temperature of the oil bath raised to l()8-l 10 C. for a further hour. Methanol (9.6 ml.) is collected. On cooling. the dark brown oil crystallires and is dissolved in ether (I20 ml.]. the ethereal solution is washed with 2 per cent sodium carbonate solution (50 ml.) and then with saturated sodium chloride solution. Evaporation of the dried ethereal solution yields 3|.2 g. of a pale yellow solid. The crude product is dissolved in boiling carbon tetrachloride (280 ml} and some solid (mainly pyrogallol) is removed by filtration. On cooling. the solution yields 24.24 g. (66.6 percent) of 2-methoxy-2-methyl- 4-hydroxy-l.B-benzodioxole. mp lll6ll)9 (1. Upon further recrystallization of the compound from carbon tetrachloride. with treatment with charcoal and activated alumina. the product melts at ll-l.5l 155 C.

Analysis calculated for H O Found: C. 59.70. H. 5 H5.

Step B: Preparation of 2-Methoxy-2-methyl-4- benzyloxy-Llbcnzodioxole To a suspension ofsodium hydride (2.4 g. 0.1 mole) in freshly distilled hexamethyl-phosphoramide [24 ml.) is added dropwise with stirring under dry nitrogen a solution of 2-methoxy2methyl-4hydroxy-l.3- bcnzodioxole (l8.2 g. ().l mole) in hexamcthylphos phoramide (36 ml.) and stirring is continued at ambient temperature until hydrogen evolution essentially ceases. Benzyl chloride (l2.65 g.. ().l mole) is added and the mixture stirred at R() C. for 5 hours. The mixture then is poured onto ice and adjusted to ca. pH 6 with acetic acid. The product is extracted with ether. and the ethereal solution washed with 2 percent sodium carbonate solution (50 ml.) and then with saturated sodium chloride solution. After drying over magnesium sulphate and then calcium sulfate. the ethereal solution is evaporated to give 2-methoxy-2-methyl-4-bcn7yloxy- 1.3-benzodioxole which can be crystallired from diisopropyl ether. Step C: Preparation of 3-bemyloxy-catechol A mixture of 2-methoxy-2-methyl-4-benzyloxy-l.3- benzodioxole (13.6 g.. 0.05 mole). methanol (21() ml.) and 5N hydrochloric acid (2H) ml.) is stirred under reflux in an atmosphere ofnitrogen for It) hours. Most of the methanol is distilled off under vacuum and the product then extracted with ether. The ethereal solution is washed with water, dried over magnesium sulfate followed by calcium sulfate and evaporated to dryness to yield the crude 3-benzyloxy-catechol which can be recrystallized from diisopropyl ether. Step D: Preparation of 3-amino4-cyano-6-ben2yloxy 3.4-dihydro2H' l .S-henzodioxepin By replacing catechol employed in Step A of Exam ple l by an equivalent quantity of 3 bemyloxycatcchol and following substantially the same procedures described in Steps A and B of Example I there are ohtained sequentially l.2-di(cyanomethoxy l-3- benzyloxybcnzene and then 3-amino-4-cyano-6- bcnzyloxy-3.4-dihydro-2Hl.S-benzodioxepin and/or the 9-benzyloxy isomer. Step E: Preparation of 3,6-dihydroxy-3- isopropylaminomethylJ.4-dihydro-2H- l ,5- benzodioxepin hydrochloride The 3-amino-4-cyano-o-benzyloxyJA'dihydro-2H- LS-henzodioxepin and/or its 9-benzyloxy isomer is converted to 3-oxo-o-benzyloxy-3.4-dihydro-2H-l,5- benzodioxepin by the procedure described in Example I Step C. and the B-keto compound then reacted with potassium cyanide by either the process of Step D of Example 1 or the alternative procedure there described to provide 3-hydroxy-3-cyano-6-benzyloxy-3,4- dihydro-ZH-lfibenzodioxepin. This product then is reduced with lithium aluminum hydride by the method 10 be employed.

TABLE VII R R3 X H o H l 0 OH Exam le 1 O 1 See Tabl 5 1 H 3E'e' s A c R1 or R o caarm Method 0 R H H R R a Ex Method For n A 1 t R R x R R3 R5 Ex. N0. Step 97 a cs ca n a -ca ca 2 1 13-)? as a (cit cca H a -ca (CH 2 57 A-B as a (crr ctca i c H- -CH (c11 2 123 c loo u (cs ZCH- (CH3) caa H -c (cm) 3 57 AB tor (LHQZCH- a tca i caa u -ca(ca 1 0-? CH v I elm .caa a ca a -ca-ca 23 A-C 2. a cs crr a a a -c(ca 3 57 A-B I 104 ca oa H -ca ca a -cH-cH -oa 24 A-B 105 ca n H a crr -ca(ca 123 c 106 a CH;,- a a H -c ca 57 A-B 107 a N02 a a a -ca-cn I 57 A-B [NI D outlined in the alternate of Step E. Example I, to give 3-hydroxy-laminomcthyl-(i-benzyloxy-3.4-dihydro- ZH-l.5bcn2odioxepin which when reacted with acetone and then reduced by the process of Step F, Example 1. there is obtained Bh-dihydroxy-B- isopropylaminomethyl-3.4-dihydro-2H l .5- bemodioxcpin hydrochloride.

Additional 3.3-disubstituted-benzodioxepins having at least one substitucnt attached to the benzcnoid moiety that can be prepared from the appropriate catechol by any of the major routes illustrated in Flow Diagram ll followed by any otthc procedures illustrated in Flow Diagram l are identified in the following Table. For convenience the catechols identified in Table Vll are eomerted to the 3oxo-ben7vodioxepin by substantially the same methods described in Example 1. Steps A through C (that is route E F G A A in Flow Diagram ll). The outer route (that is E F 8 A] described in Examples l08 and I09 could have tit] Example l08 3-Hyd roxy-3-isopropylaminomethyl-3 4-dihydro-2H- LS-benzodi-oxepin Hydrochloride 37 Step B: Preparation of 3-oxo-4-carhomethoxy3.4- dihydro-ZH- l .S-hcnzodioxepin.

Potassium t.-hutoxide U58 g.) dissolved in DMSO 130 ml.) is added dropwise over a 45 minute period (0.4 mole) is stirred until solution is effected. then the solution treated with 2-hromo-2-( Z-pyridyl )-acetic acid (21.6 g. 0.l mole). and refluxed for 20 hours. The cooled solution is taken to neutrality and the diacid to l.2bis carbomethoxymcthoxyhenzene (18.3 g.) in 5 crysmmzfid from hcnzcnc h P' DMSO (30 ml.) under an atmosphere of nitrogen. The y thoxyplienoxy)-acctic acid.

mixture then is stirred 3 hours at ambient temperature Step Bi Prcpammm methyl and a mixture of acetic acid (l6 ml.) and water (200 fi l'ioxymethoxyphenoxyi acetate ml.) is added. The reaction mixture is extracted with i i i i ii Miti i f l i i benzene. the powdery material removed by filtration m P uencsu m mu I is refluxed for 24 hours and the solvent then removed. and the benzene then dried over magnesium sulfate and and replaced by diethyl ether. The ethereal solution is the benzene then evaporated leaving 3-oxo-4- washed with water. 5 percent sodium bicarbonate. then carbomethoxy-3.4-dihydro-2H-l.fi-henzodioxepin that I i x I i h v d in the funnwin p without purific'nkm again with water. dt'lLdOHJ an ydrous sodium su tatc, g? C P g f 2 14d H 1 s 15 and evaporated to give methyl 2-(2-pyridyl)-2-[2- d" 0 1 y mi carbomethoxymethoxyphenoxy) acetate.

enzo ioxpin. Sm p i "l 7 w r I I V p reparation of pyridyl) 3 oxo 3.4 3-Oxo-4-carhomcthoxy3.4-dihydro-?H- l .5- dihydm 2H 1 jhcnzudioxwin benzodioxepin 1 l() g.) is added to a mixture ofmetha- B f u x I h d w 1 H 10 ml concentrated h 'drochloric acid (St) m] U Owing bu humid t L iv no v scribed in Example I08. Steps B and C. but substituting and water (l60 ml.) and the mixture then is refluxed methyl 2 (lmfldyl) 2 (lmrbomclhnmcthuxy for 18 hours. The product is extracted with ether. and phenoxy) ucemtc lhc l3 hi5 (wrhomthnxvmb the ether extract washed with four 50 ml. portions of thoxwbenzene there is Obtained Sequential 3 3 sodium bicarbonate solution, then twice with 50 m pyridyl)-3-0XO-4-CzirbOmt3lh0X\'-3 Jdih dr yZI-L]jportions of water. After drying the washed ether exbcnzodioxepin and the 3. 3 y g m tract over magnesium sulfate and evaporation to redihydro-ZH-l,S-henzodioxepin. move the solvent there is obtained 3-oxo-3A-dihydro- Step 1 prcpumiinn f 3 3- -3. 3- l -5-benludloxcpinisopropylaininomethyl 3 4-dihydro-1H-l t5- Step D: Preparation of 3-hydroxy-3- 3U benzodioxpin hydrochloride p py y y This product is prepared by replacing the 3-oxobenzodioxepin hydrochloride benzodioxepin employed in Example I. Step D. by an The 3-oxo-3,4-dihydro-2H-l.S-henzodioxepin is conequivalent quantity of 2(2p vridy|)-3-oxo-3.4- verted to the desired 3-hydroxy-3- dihydroQl-Ll.i-benzodioxcpin and then employing the isopropylaminomethyl-3,4-dihydro-2H-l.5- other reactants and reaction conditions of Steps D benzodioxepin hydrochloride hy the procedures dethmugh F or Examplc scribed in Example l. Other compounds exemplary of those that can be prepared by the processes called for in Example 109 Example are identified in Table lll. These Z-suhstituted- 'l "W Q l 4t) benzodioxepins are made by replacing the Z-hromo-l dlhydmQHsibcnzodmxepm hydrochlundc' (Z-pyridyH-acetic acid employed in Step A of Example Step A: Preparation of 2-(2-Pyridyl)2-(2- It); by an equivalent quantity of the haloacetic acid carboxymethoxyphenoxy)acetic acid identified in the following table and then following the A mixture of Z-hydroxyphenoxy acetic acid l6.8 g. procedures of Example l0) Steps A and B. Example 0.1 mole) and 80 ml. of 5N aqueous sodium hydroxide 108. Steps 8 and C and finally Steps D through F of x an: v!!! [ISM Zxam lo 109 9 I B Exarple 108 W .Iteps B C a R H I a {\I O Exgple l ll 0 ca m 5 F 0 0-01 ii ii Ex. .\'o. X It Carbonyl Reactarit ft L) (CH1) c-o -cii cii ,i 1

iii a: (9- (CH c-o -ci-itcii ,i

112 a: (C11,) ,c-o -cu mm 2 1:: C: ca 011- icim c-o -ciiicii,i,

ca, 114 Dr f HO-O-CH2C-O -cii( :ii,i-cii,--oii 

1. A 3,3-DISUBSTIITUTED -BENZODIOXEPIN HAVING THE STRUCTURE
 2. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents lower alkyl and R6 has the meaning assigned in claim
 3. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R2,R3,R4, and R5 each represent hydrogen and R6 has the meaning assigned in claim
 1. 4. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R,R1,X,X1,R3 and R5 each represent hydrogen and R2,R4 and R6 have the meaning assigned to each in claim
 1. 5. 3-Hydroxy-3-hydroxymethyl-3,4-dihydro-2H-1,5-benzodioxepin.
 6. A 7-substituted-3''-lower alkyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5''-oxazolidin-2''-one wherein the 7-substituent is selected from hydrogen, hydroxy, nitro, lower alkylsulfonamido, lower alkoxycarboxamido, mono- and di-lower alkylamino.
 7. A product as in claim 3 wherein R6 is 3-(3,4-methylenedioxyphenyl)-2-propyl. 